Craniofacial reconstruction is required after trauma, tumors, and for craniofacial disorders. Bone grafts and synthetic scaffolds have resulted in limited success. Bone morphogenetic proteins (BMPs) stimulate the production of bone and cartilage, and are necessary for tooth development, palate closure and normal craniofacial development. BMPs are also required for bone repair and can stimulate stem cells to take on cartilage and bone fate. Our hypothesis is that ion channel activity regulates BMP secretion in mammals in a conserved mechanism. If our hypothesis proves correct, electrical stimuli or small molecules that affect ion channel activity may provide the ability to control release of BMP for proper bone and tooth development and regeneration. Our long-term goal is to use a novel approach of manipulating cells to secrete endogenous BMP to encourage craniofacial bone development. We recently discovered that ion channels control the secretion of BMP in the fruit fly. The first step towards this goal is to determine how ion channels contribute to craniofacial development in mammals. In this proposal, we use the Kir2.1 potassium (K+) channel to determine the molecular connection between ion conductivity and developmental signaling in mammals. Humans and mice with mutations in Kir2.1 have congenital craniofacial defects including cleft palate, dental defects, and micrognathia showing that this channel plays an essential role in craniofacial development. Aim 1 defines the developmental processes in palate closure that require Kir2.1 (proliferation, apoptosis, palate shelf fusion, differentiation, and/or ossification) and tests the hypothesis that Kir2.1 modulates BMP signaling in mice. Aim 2 identifies the cell types that require Kir2.1 for palate development. In Aim 3, we manipulate ion channel function to test the hypothesis that cellular depolarization can increase BMP secretion. The proposed experiments will lay a new foundation for future studies to harness the potential of ion channels in non- excitable cells to stimulate tissue growth and regeneration.